Fungal Meningitis

Hafiz Muhammad Waqas Siddque (1), Talha Nazir (2), Junaid S Kalia (3)
  1. King Edward Medical University
  1. King Edward Medical University, Pakistan
  1. Founder AINeuroCare.com


Introduction

  • Meningitis is defined as the inflammation of the fluid and membranes (meninges) surrounding the brain and spinal cord.
  • The causes of meningitis may be infectious or non-infectious
  • Infectious causes include viral, bacterial, fungal, or parasitic
  • The worldwide incidence of cryptococcal meningitis alone in HIV/AIDS patients was estimated at 223,100 cases per year worldwide, resulting in 181,100 annual deaths in 2014

Pathophysiology

  • In most cases, fungal spores are inhaled during breathing which causes initial pulmonary infection.
  • The subsequent seeding of infection to the brain or spinal cord causes meningitis.
  • Candida is normal body flora, and it can cause meningitis in certain individuals with immunodeficiency,
  • It can be also directly inoculated into CNS during neurosurgical procedures.
  • It is not contagious from person to person

Etiology

The most common causative organisms, areas of distribution, and primary source of infection are given in Table 1.

Table 1: Common Fungi associated with meningitis

Common Fungi associated with meningitis
Type of Fungus
Area of Distribution
Source of Infection
Primary Site of Infection
Worldwide
Soil, Pigeon Droppings
Pulmonary
Ohio and Mississippi River Valleys
Bird or Bat Droppings
Pulmonary
Arizona and California
Soil, Dust
Pulmonary
Eastern and Central US, Great Lakes
Moist Soil, Decaying Wood and Leaves
Pulmonary
Worldwide
Normal Flora
Blood, Any Organ, Direct Seeding
Worldwide
Soil, Landscaping and Rose Gardening
Skin and Soft Tissue
Tropical and Subtropical Regions
Soil and Decaying vegetation
Paranasal Sinuses, Direct Seeding

Risk Factors

  • Immunodeficiency
    • Solid-organ transplantation
    • Stem cell transplantation
    • Steroids
    • TNF inhibitors
  • AIDS
  • Diabetes Myelitis
  • Low-birth-weight neonates
  • Post-neurosurgery patients
  • Alcoholics
  • Malignancies

Clinical Manifestations

  • Fever
  • Headache
  • Neck Rigidity
  • Nausea and Vomiting
  • Confusion
  • Photophobia
  • Seizures
  • Muscle aches
  • Dry cough
  • CN palsies
  • Lethargy and Coma
  • Ataxia
  • Other focal neurologic deficits

Differential Diagnosis

Fungal meningitis must be differentiated from other diseases like
  • Bacterial Meningitis
  • Viral Meningitis
  • Tubercular Meningitis
  • Encephalitis
  • Brain abscess
  • Syphilis
  • Malignancies

Diagnosis and Management

  • Fungal meningitis needs an extensive workup for diagnosis

Laboratory tests

  • Blood work may show peripheral leukocytosis, lymphocytosis, and increased inflammatory markers like ESR and CRP.
  • Lumbar puncture shows increased opening pressure usually greater than 200mm of H2O.
  • Typical CSF findings in fungal meningitis are shown in Table 2
 

Table 2: Cerebrospinal fluid analysis

Cerebrospinal fluid analysis
CSF Parameters
Bacterial Meningitis
Viral Meningitis
Fungal Meningitis
Tuberculous Meningitis
>180
Often Normal
Variable
>180
1000—10,000 Range <100—20,000
<300 Range <100—1000
20—500 Variable, dependent upon fungus
50—500 Range 50—4000
>80
<20
Usually <50
20
100--500
Often Normal
Elevated
150--200
<40
>40
Usually  <40
<40

Specific laboratory tests

The specific laboratory tests, imaging studies, and treatment plans are in accordance with causative agent

Cryptococcal meningitis

Diagnosis
  • CSF cryptococcal antigen testing by latex agglutination has a sensitivity and specificity of >90%.
  • CSF culture is also positive after 5-7 days.
  • Cryptococcal antigen testing is the gold standard
Treatment
  • Induction therapy: Amphotericin B 0.7–1.0 mg/kg per day intravenously combined with flucytosine 100mg/kg/day for 2 weeks.
  • Consolidation phase: Fluconazole 400 – 800 mg/day for at least 8 weeks.
  • Maintenance therapy: Fluconazole 200 mg/day for ≥1 year from initiation of therapy.
Complications
  • Immune reconstitution inflammatory syndrome (IRIS): Seen in HIV-infected individuals

Histoplasma meningitis

Diagnosis
  • Histoplasma antigen is positive in the urine of >90% of the patients while in serum of 50%.
  • A fourfold increase in antibody level during serial antibody testing suggests active infection.
  • Complement fixation against Histoplasma antigen in CSF diagnoses the Histoplasma meningitis even if the culture is negative.
  • Methenamine silver staining of histopathological tissue shows oval narrow-based budding yeast.
Treatment
  • Induction therapy: Liposomal amphotericin B 5 mg/kg intravenously daily for four to six weeks.
  • Consolidation phase: Oral itraconazole, 200 mg two to three times a day for ≥12 months

Coccidioides meningitis

Diagnosis
  • CSF analysis is of prime importance in the diagnosis and management of coccidiosis. Eosinophils, if present, are highly suggestive of coccidioides meningitis.
  • Complement fixation antibody in CSF is the most reliable test.
  • The skin lesions, if present, are the important source of histopathology
Treatment
  • Fluconazole 400 to 800 mg daily is the preferred treatment regimen
  • If treatment fails, itraconazole or intrathecal Amphotericin B can also be used.
  • Suppression therapy: Lifelong, especially in immunocompromised individuals
Complications
  • Hydrocephalus: Managed by VP shunts

Blastomycosis meningitis

Diagnosis
  • Biopsy of extracranial lesion of skin, bone, or lung shows broad-based budding yeast.
Treatment
  • Induction therapy: Lipid formulation of amphotericin B 5 mg/kg per day for 4 to 6 weeks,
  • Consolidation phase: Oral azole for about 12 months.
  • Suppression therapy: Lifelong, especially in an immunocompromised individual

Candida meningitis:

Diagnosis
  • CSF culture may be helpful in some cases
Treatment
  • Induction therapy: Liposomal amphotericin B 5 mg/kg intravenously once daily with or without flucytosine 25 mg/kg orally four times daily for several weeks.
  • Consolidation phase: Fluconazole 400 to 800 mg 6 to 12 mg/kg oral daily as a step-down therapy

Sporothrix meningitis:

Diagnosis
  • Culture is the most sensitive and gold standard test.
  • Skin lesion biopsy is used for histopathological diagnosis.
  • Beta D-glucan essay is also positive in different types of invasive fungal infection.
Treatment
  • Induction therapy: Liposomal amphotericin B 3 to 5 mg/kg/day
  • Consolidation phase: Itraconazole 200 mg twice daily for 12 months

Table-3: Overview of drugs for fungal infections of the CNS

Derived from: Góralska, K., Blaszkowska, J., & Dzikowiec, M. (2018). Neuroinfections caused by fungi. Infection, 0(0), 1–17. https://doi.org/10.1007/s15010-018-1152-2

Complications

CT scan and MRI with contrast done to rule out the complications
  • Hydrocephalus
  • Cranial nerve palsies
  • Brain abscesses
  • Frequent relapses

Prevention

For Prevention, the immunocompromised individual must take the following measures,
  • Avoid construction or excavation sites, especially when there is a risk for dust exposure.
  • Limit outdoor activity during dust and wind storms
  • Avoid gardening, landscaping.
  • Take prophylactic antifungal medication when recommended.

Further Reading

  • Pagliano P, Esposito S, Ascione T, Spera AM. Burden of fungal meningitis. Future Microbiol. 2020;15:469-472. doi:10.2217/fmb-2020-000
  • Raman Sharma R. Fungal infections of the nervous system: Current perspective and controversies in management. International Journal of Surgery. 2010;8(8):591-601.

Bibliography

  • Abassi, M., Boulware, D. R., & Rhein, J. (2015). Cryptococcal Meningitis: Diagnosis and Management Update. Current tropical medicine reports2(2), 90–99. https://doi.org/10.1007/s40475-015-0046-y
  • Fungal Meningitis. Cdc.gov. https://www.cdc.gov/meningitis/fungal.html. Published 2021. Accessed August 26, 2021.
  • Charles P. Davis, MD, PhD. Fungal Meningitis. Medicinenet.com. https://www.medicinenet.com/fungal_meningitis/article.htm#fungal_meningitis_facts. Published 2021. Accessed August 30, 2021.
  • Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV. Clinicalinfo.hiv.gov. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/whats-new-guidelines. Published 2021. Accessed August 30, 2021.
  • Kauffman, MD C, Marr, MD K, Baron, MD, DTMH E. Candida infections of the central nervous system. Uptodate.com. https://www.uptodate.com/contents/candida-infections-of-the-central-nervous-system. Published 2021. Accessed August 25, 2021.
  • Mayo Clinic Staff. Valley fever - Symptoms and causes. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/valley-fever/symptoms-causes/syc-20378761. Published 2020. Accessed August 25, 2021.
  • Rajasingham, R., Smith, R. M., Park, B. J., Jarvis, J. N., Govender, N. P., Chiller, T. M., Denning, D. W., Loyse, A., & Boulware, D. R. (2017). Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis. The Lancet. Infectious diseases17(8), 873–881. https://doi.org/10.1016/S1473-3099(17)30243-8
  • Salardini A, Biller J. The Hospital Neurology Book. McGraw-Hill Education, Inc.; 2016:92-96.
  • Slavoski LA, Tunkel AR. Therapy of fungal meningitis. Clin Neuropharmacol. 1995 Apr;18(2):95-112. doi: 10.1097/00002826-199504000-00001. PMID: 8635178.
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